Intravenous Antimicrobials: Is It Time to Push?

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IV antimicrobials are a commonly utilized resource in a variety of clinical settings and are typically administered as IV piggyback solutions given over at least 30 minutes. Alternative IV antimicrobial administration strategies exist, such as IV push. IV push is characterized as a rapid administration (typically over 3-5 minutes) of drug via IV syringe in minimal fluid volume. Scenarios may exist where IV push antimicrobial administration is advantageous; these include, but may not be limited to, IV fluid shortages, rapid administration of antimicrobials in the emergency department (ED), first doses of antimicrobials in sepsis, and outpatient parenteral antimicrobial therapy (OPAT).

Key manufacturing infrastructures were significantly affected by Hurricane Maria in 2017 and more recently by Hurricane Helene in 2024. These facilities served as major sources for small and large volume parenteral fluids, thus the impact from these natural disasters resulted in severe IV fluids shortages.^1,2 In fact, IV fluid shortages predate these events and have affected supply chains since 2007.³ Health systems and medical providers have sought out measures to deal with these impactful fluid shortages.^4,5 As a result, various systems have implemented IV push administration of antimicrobials.^6,7

The ED is a practice area where quick administration of medications is crucial to aid in patient care, facilitate throughput, and aid in nursing satisfaction. The utilization of IV push, especially for first antimicrobial doses given in the ED and in patients with concern for sepsis, can significantly aid providers caring for these patients.⁸ The 2021 Surviving Sepsis Campaign international guidelines state antibiotic administration should occur within the first hour following recognition of sepsis.⁹ Additionally, a 7.6% decrease in survival has been shown to occur every hour that patients with septic shock do not receive antibiotic therapy during the first 6 hours after onset of hypotension.¹⁰ Utilization of IV push antimicrobials in the ED setting can facilitate drug administration in these crucial scenarios.

Another area of great interest for IV push administration is the outpatient setting.¹¹ OPAT programs look to allow patients to deliver medications in the most efficient way possible, as administration is typically done by the patient themselves or another caregiver that may not have specific medical training. Administration by IV push potentially simplifies this process and cuts down on the time required for patients to self-administer medications.¹² For interested healthcare providers who wish to learn more about OPAT and drug administration methods in the home, Loriaux et al published an excellent narrative summarizing these concepts along with advantages and disadvantages of each method.¹²

An added benefit of IV push antimicrobials is cost savings. Utilizing IV push reduces the need for and costs associated with IV tubing, IV bags, staff time to prepare the IV infusion, and equipment such as infusion pumps.⁸ McLaughlin et al demonstrated an estimated $40,000 cost savings due to lower supply costs with implementation of a first-dose cephalosporin IV push administration in the ED.¹³ Other studies have also demonstrated cost savings with implementation of IV push with antimicrobials.^14-16

Even with the benefits of IV push antimicrobial administration, potential safety issues should not be overlooked. The Institute for Safe Medication Practices (ISMP) published a safe practice guideline for adult IV push medication administration.¹⁷ Factors highlighted in this guideline that may result in an increased risk of IV push medication errors include lack of direction for the rate of IV push administration, ambiguous and undefined terminology (ie, “IV push”, “IV bolus”, “IV over X minutes”, “slow IV push”), and lack of training/experience with IV push administration for undergraduates in professional nursing programs. There have also been concerns raised about patient safety when receiving medications as IV push, such as pain at the injection site or thrombophlebitis from more concentrated solutions. While these concerns are valid with IV push administration of antimicrobials, safety data exist to support their use without an increase in adverse events. In the ED, Rahbar et al showed no significant difference in adverse drug reactions of antibiotics administered as IV push vs IV piggyback (18.9 % vs 11.8 %, 95 % CI –9.5 to 23.8).¹⁸ Similarly, Academia et al showed no difference in adverse drug reactions between IV push and IV piggyback antibiotic administration (1.7 % vs 2.6 %, p > 0.05).¹⁵

A comprehensive review of data on IV push administration of individuals drugs is outside the scope of this article. A 2018 publication by Spencer et al provides a thorough narrative review of available data on IV push and slow infusion administration of antibiotics; we would refer the reader to this publication for an in-depth analysis of specific drugs.¹⁹ Beta-lactam antibiotics have the most data and clinical experience to support IV push administration. Beta-lactams demonstrate time dependent killing & target optimization of time over the minimum inhibitory concentration (MIC) of the organism to enhance efficacy;²⁰ thus, prolonged (administered over 3-4 hours) and continuous (administered over 24 hours) infusions are often employed. Additionally, prolonged infusions are utilized to combat organisms with increasing MICs. These key factors for beta-lactams would not suggest IV push administration would be ideal. Liu et al evaluated pharmacodynamic effects of cefepime regimens given as IV push or intermittent infusion.²¹ They showed that at elevated MICs (≥ 2 mg/L), cefepime may be less efficacious given as IV push based on decreased probability of target attainment. However, Butterfield-Cowper et al showed minimal differences in free time over MIC (ft>MIC) between IV push and intermittent infusion with several beta-lactams.²² While clinical impact was not assessed in these studies, it suggests the use of IV push beta-lactams may be considered in patients with infections caused by highly susceptible organisms.

In addition to pharmacokinetic/pharmacodynamic and safety data discussed, there is clinical outcomes data to consider regarding IV push antimicrobials. As highlighted above, the ED may benefit from IV push antimicrobials due to the high proportion of patients presenting with sepsis and need for timely antimicrobial administration. Several retrospective studies have investigated IV push beta-lactam administration in the ED in patients with sepsis or septic shock. Studies by Gregorowicz et al. and Lim et al. found no differences in overall mortality, but quicker time to administration (and completion) of the beta-lactam.^23,24 Given the logistical benefits of administration by IV push, it is reasonable to consider IV push beta-lactams in the ED or as a first dose in septic patients based on currently available literature.

Other studies have examined the impact of more prolonged utilization of IV push antimicrobials in patients with documented infections. Marsh et al. examined 213 patients with Gram-negative bacteremia treated with at least two days of IV push vs IV piggyback cefepime or meropenem. Fifteen (14%) patients in the IV piggyback group and 11 (10%) patients in the IV push group met the primary outcome of escalation of therapy (p =0.36).²⁵ No other significant differences were noted in outcomes such as recurrence of bacteremia, time to defervescence, and in-hospital mortality.

Notably, the majority of patients had E. coli or K pneumoniae bloodstream infections from a urinary or intra-abdominal source. The authors noted the need for further examination of IV push dosing strategies for the treatment of organisms with higher MICs, such as Pseudomonas aeruginosa, or deep-seated sources of infection. More recent literature has looked to examine the critically ill population, especially as there is a potential for more variable PK/PD parameters in these patients. Sherman et al observed a higher rate of treatment failure (37.8% vs 19.5%; p <0.001) in a retrospective analysis of 201 patients receiving IV push ceftriaxone vs 200 patients receiving IV piggyback ceftriaxone for at least 72 hours and admitted to the intensive care unit (ICU).²⁶ Despite several sensitivity analyses to minimize patients with infections due to ceftriaxone non-susceptible organisms, outcomes remained worse in the IV push group.

Smith et al saw similar results in their retrospective trial examining patients receiving at least 72 hours of empiric cefepime in the ICU. Treatment failure was observed at a higher rate in patients receiving IV push vs IV piggyback administration (27% vs 18%, p=0.109), with IV push administration demonstrating a 2.37 OR (95% CI 1.143-4.914) associated with treatment failure in a multivariate analysis.²⁷

Johnson et al examined time to clinical stability (resolution of systemic inflammatory response syndrome (SIRS) criteria) in 100 patients admitted to the ICU who received IV push vs extended infusion (EI) (3 hours) meropenem for at least 48 hours. In contrast to the prior mentioned studies, there was no difference between the two groups in the percentage of patients who achieved stabilization (48% in IV push vs 44% in EI); however, a faster median time to clinical stabilization was seen in the EI group (66.2 hours vs 20.4 hours; p = 0.01).²⁸ While these trials are single center, retrospective analyses with limitations, the evidence from these studies, as well as the lack of compelling other clinical data in critically ill patients, brings pause to the idea that IV push antimicrobials consistently provide optimal clinical outcomes for patients. Many questions regarding the treatment of specific organisms and infectious sources with IV push antimicrobials remain unanswered at this time.

Evaluating data on IV push in the outpatient setting, Yagnik et al examined 200 patients receiving antimicrobials via self-administered OPAT, with 95 receiving IV piggyback infusions and 105 receiving IV push via prefilled syringes. The retrospective study observed a shorter length of hospitalization prior to OPAT in the IV push group (11 vs 12 days, p =0.03) and noted no differences in clinical outcomes including readmission rates at 30 days and 1 year, ED visits at 30 days and 1 year, or mortality⁷. Notably, patients also demonstrated quicker competency with IV push vs IV piggyback administration.

Based on the currently available literature, IV push antimicrobials offer various advantages for patients and can be considered in a variety of situations, such as the ED, first antimicrobial doses in patients with concerns for sepsis, during situations of IV fluid shortages, treatment of uncomplicated infections, and for OPAT. Patients with critical illness, infections due to difficult to treat organisms, or deep-seated infections should be assessed on a case-by-case basis to ensure the appropriate method of administration for antimicrobials is chosen.

The Society of Infectious Diseases Pharmacists (SIDP) is an association of pharmacists and other allied healthcare professionals who are committed to promoting the appropriate use of antimicrobial agents and supporting practice, teaching, and research in infectious diseases. We aim to advance infectious diseases pharmacy and lead antimicrobial stewardship in order to optimize the care of patients. To learn more about SIDP, visit sidp.org

References

1. Food and Drug Administration. FDA Commissioner Scott Gottlieb, M.D., updates on some ongoing shortages related to IV fluids. January 16, 2018. Accessed 20 December 2024. https://www.fda.gov/news-events/press-announcements/fda-commissioner-scott-gottlieb-md-updates-some-ongoing-shortages-related-iv-fluids
2. Food and Drug Administration. Hurricane Helene: Baxter's manufacturing recovery in North Carolina. December 12, 2024. Accessed 20 December 2024. https://www.fda.gov/drugs/updates-2024-hurricane-season/hurricane-helene-baxters-manufacturing-recovery-north-carolina
3. Mazer-Amirshahi M, Fox ER. Saline shortages – many causes, no simple solution. N Eng J Med. 2018; 378(16):1472-1474. doi: 10.1056/NEJMp1800347
4. National Home Infusion Association (NHIA). Guidance for addressing product shortages during disruptions in manufacturing. October 8, 2024. https://nhia.org/wp-content/uploads/2024/10/Guidance-Document-Disruptions-in-Manufacturing.pdf
5. American Society of Health-System Pharmacists (ASHP). Small- and Large-Volume Fluid Shortages – Suggestions for Management and Conservation. November 25, 2024. https://www.ashp.org/-/media/assets/drug-shortages/docs/drug-resources-conservation-strategies-iv-fluids.pdf
6. Pettit NN, Nguyen CT, Stahle S, Wong M, Bastow S, Pisano J. Implementing i.v. push administration of piperacillin-tazobactam in response to shortage of small-volume infusion bags. Am J Health-Syst Pharm. 2018;75(18):1358-1359. doi: 10.2146/ajhp180163
7. Yagnik KJ, Brown LS, Saad HA, et al. Implementation of IV push antibiotics for outpatients during a national fluid shortage following Hurricane Maria. Open Forum Infect Dis. 2022;9(5):ofac117. doi: 10.1093/ofid/ofac117
8. Rech MA, Gottlieb M. Intravenous push antibiotics should be administered in the emergency department. Ann Emerg Med. 2021;78(3):384-385. doi: 10.1016/j.annemergmed.2021.03.021
9. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021;49(11): e1063-e1143. doi: 10.1097/CCM.0000000000005337
10. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596. doi: 10.1097/01.CCM.0000217961.75225.E9
11. Infectious Diseases Society of America (IDSA). Handbook of Outpatient Parenteral Antimicrobial Therapy for Infectious Diseases, 3^rd edition. 2016. https://www.idsociety.org/globalassets/idsa/clinical-affairs/opat_epub_finalv3.pdf
12. Loriaux A, Desmond M, Li PC. A primer on home infusion administration methods. Open Forum Infect Dis. 2022; 9(12):ofac525. doi: 10.1093/ofid/ofac525
13. McLaughlin JM, Scott RA, Koenig SL, Mueller SW. Intravenous push cephalosporin antibiotics in the emergency department: a practice improvement project. Adv Emerg Nurs J. 2017;39(4):295-299. doi: 10.1097/TME.0000000000000160
14. Brady RE, Giordullo EL, Harvey CA, et al. Intravenous push antibiotics in the emergency department: education and implementation. Am J Health-Syst Pharm. 2024;81(12):531-538. doi: 10.1093/ajhp/zxae039
15. Academia EC, Jenrette JE, Mueller SW, McLaughlin JM. Evaluation of first-dose, intravenous push penicillins and carbapenems in the emergency department. J Pharm Pract. 2022;35(3):369-376. doi: 10.1177/0897190020977758
16. Ambrose PG, Bui KG, Richardson MA, Quintiliani R, Nightingale C. Pharmacoeconomic analysis of intravenous push vs slow infusion of β-lactam antibiotics. Clin Drug Invest. 1999;17(5):407-410. doi.org/10.2165/00044011-199917050-00007
17. Institute for Safe Medication Practices. ISMP Safe Practice Guidelines for Adult IV Push Medications. 2015. https://www.ismp.org/sites/default/files/attachments/2017-11/ISMP97-Guidelines-071415-3.%20FINAL.pdf
18. Rahbar A, David J, Promlap J, Hara J, Zitek T, Lee P. Safety comparison of antibiotics administered via intravenous push versus intravenous piggyback to adult patients in the emergency department. Ann Emer Med. 2021;78(4, Suppl 1):S71.
19. Spencer S, Ipema H, Hartke P, et al. Intravenous push administration of antibiotics: literature and considerations. Hosp Pharm. 2018. 53(3):157-169. doi: 10.1177/0018578718760257
20. Ambrose PG, Bhavnani SM, Rubino CM, et al. Pharmacokinetics-pharmacodynamics of antimicrobial therapy: it’s not just for mice anymore. Clin Infect Dis. 2007;44(1):79-86. doi: 10.1086/510079
21. Liu J, Rhodes NJ, Roberts JA, et al. β-lactam dosing strategies: Think before you push. Int J Antimicrob Agents. 2020;56(5):106151. doi: 10.1016/j.ijantimicag.2020.106151
22. Butterfield-Cowper JM, Burgner K. Effects of i.v. push administration on β-lactam pharmacodynamics. Am J Health-Syst Pharm. 2017;74(9):e170-e175. doi: 10.2146/ajhp150883
23. Gregorowicz AJ, Costello PG, Gajdosik DA, et al. Effect of IV push antibiotic administration on antibiotic therapy delays in sepsis. Crit Care Med. 2020;48(8):1175-1179. doi:10.1097/CCM.0000000000004430
24. Lim SY, Baek S, Jo YH, et al. Effect of intravenous push and piggyback administration of ceftriaxone on mortality in sepsis. J Emerg Med. 2024;66(5):e632-e641. doi:10.1016/j.jemermed.2023.12.008
25. Marsh K, Dubrovskaya Y, Jen SP, et al. Intravenous push versus intravenous piggyback beta-lactams for the empiric management of gram-negative bacteremia. J Clin Pharm Ther. 2021;46(2):373–381. doi: 10.1111/jcpt.13291
26. Sherman ER, Ta NH, Branan TN, et al. Evaluation of the efficacy of intravenous push and intravenous piggyback ceftriaxone in critically ill patients. Antibiotics. 2024;13(10):921. doi: 10.3390/antibiotics13100921
27. Smith SE, Halbig Z, Fox NR, Bland CM, Branan TN. Outcomes of intravenous push versus intermittent infusion administration of cefepime in critically ill patients. Antibiotics. 2023;12(6):996. doi: 10.3390/antibiotics12060996
28. Johnson EG, Maki Ortiz K, Adams DT, et al. A retrospective analysis of intravenous push versus extended infusion meropenem in critically ill patients. Antibiotics. 2024;13(9):835. doi:10.3390/antibiotics13090835